Effects of interactions between common genetic variants and alcohol consumption on colorectal cancer risk

Abstract

BackgroundGenome-wide association studies (GWAS) have identified approximately 40 common genetic loci associated with colorectal cancer risk. To investigate possible gene-environment interactions (GEIs) between GWAS-identified single-nucleotide polymorphisms (SNPs) and alcohol consumption with respect to colorectal cancer, a hospital-based case-control study was conducted.ResultsHigher levels of alcohol consumption as calculated based on a standardized definition of a drink (1 drink=12.5g of ethanol) were associated with increased risk of colorectal cancer (OR=2.47, 95% CI=1.62-3.76 for heavy drinkers [>50g/day] compared to never drinkers; ptrend<0.01). SNP rs6687758 near the DUSP10 gene at 1q41 had a statistically significant interaction with alcohol consumption in analyses of standardized drinks (p=4.6×10-3), although this did not surpass the corrected threshold for multiple testing. When stratified by alcohol consumption levels, in an additive model the risk of colorectal cancer associated with the G allele of rs6687758 tended to increase among individuals in the heavier alcohol consumption strata. A statistically significant association between rs6687758 and colorectal cancer risk was observed among moderate alcohol drinkers who consumed between >12.5 and ≤50g of alcohol per day (OR=1.46, 95% CI=1.01-2.11).MethodsA total of 2,109 subjects (703 colorectal cancer patients and 1,406 healthy controls) were recruited from the Korean National Cancer Center. For genotyping, 30 GWAS-identified SNPs were selected. A logistic regression model was used to evaluate associations of SNPs and alcohol consumption with colorectal cancer risk. We also tested GEIs between SNPs and alcohol consumption using a logistic model with multiplicative interaction terms.ConclusionsOur results suggest that SNP rs6687758 at 1q41 may interact with alcohol consumption in the etiology of colorectal cancer.

Evaluation of gene-environment interactions for colorectal cancer susceptibility loci using case-only and case-control designs

“…This may be due to ethnic differences or limited power to detect interactions. We previously reported on G × Es involving GWAS-identified colorectal cancer susceptibility loci with age at cancer onset [13], smoking [11], and alcohol consumption [12] using a conventional method of detecting interactions. In the current analysis, we combined the case-only, case-control, and control-only study designs, suggesting that the results were more powerful and less biased.…”

“…To investigate the potential contribution of G × Es to colorectal cancer, several studies have evaluated G × Es for colorectal cancer susceptibility loci identified by previous GWAS [6–13] and at a genome-wide level [14]. Most studies have adopted a case-control study design to study G × Es [6–12], which has the advantage of being relatively robust and maintaining a desired type I error rate [15]. Few studies on G × Es have used a case-only design for colorectal cancer [13, 14].…”

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers.

“…Also, some polymorphisms of these two enzymes are associated with imbibers' enhanced or attenuated drinking behavior. The distribution of these polymorphisms varies among ethnic and geographical groups, adding complexity to the unveiling of their impact on pathologies, including cancer [174][175][176][177][178][179][180]. Cancer cells of alcohol metabolizing organs of the gastrointestinal system show activated ADH and attenuated ALDH activities, compared to healthy tissues.…”

“…Additional gene variants of proteins (phosphatases, phospholipases, kinases, receptors, DNA-repair enzymes) are statistically associated with developing different types of cancer in the context of alcohol drinking [178,210,[226][227][228].…”

The Dual-Specificity Phosphatase 10 (DUSP10): Its Role in Cancer, Inflammation, and Immunity

“…Another SNP (rs6687758) located downstream of DUSP10 is associated with tooth agenesis, which in the family history of cancer positively correlated with a specific haplotype for this polymorphism [52]. Moreover, the last described SNP is a common genetic variant near DUSP10 that increases CRC risk in alcohol consumers in Korean population [53]. These studies support the idea that enhanced DUSP10 is related with CRC risk, and specific polymorphisms that modify its levels could alter the activity of direct DUSP10-targets or other important pathways for the tumour.…”